Abstract

1320

Purpose: to evaluate the clinical features and outcomes of Breast Cancer (BC) patients with genetic susceptibility to this disease and to address the question of the contribution of BRCA-1 germline mutation to the phenotype of these tumors. Patients and methods: we reviewed the clinical and pathological records of 144 women with autosomal dominant inheritance of breast (+/− ovarian) cancer risk, consecutively seen at the Genetic Oncology Service of the University Parma Hospital between June 1999 and September 2003. All women underwent full genetic counseling. Of these, 101 selected patients with high probability of having a germ-line, cancer-predisposing mutation (high risk group), were tested for BRCA-1 mutation analysis. Exon 11 was screened for BRCA1 mutations using Protein Truncation Test (PTT); mutations detected by PTT were confirmed by Direct Sequencing (DS). All the other exons were analyzed by DS. Results: The two different risk groups had similar clinical outcomes. Of the 57 patients with completed mutation analysis, 44 (77%) patients had wild-type BRCA-1, 8 (14%) had variants of unclear significance, 5 (8%) had deleterious mutations in BRCA-1. With regard to entry criteria for BRCA-1 genetic testing, mutations were detected in 5% (1/20), 2,5% (1/41), 16% (2/12) and 16% (1/6) of women with family history, early-onset BC (< 40 years), Breast-Ovarian Cancer (BOC) and early-onset plus Bilateral Breast Cancer, respectively. BRCA-1 Associated Breast Cancers (BABC) were more likely to have histological grade 3 and high proliferation rate than cases in women without mutations (40% v 27%; 60% v 45%). These differences were not statistically significant. BABC were significantly more likely to be estrogen receptor-negative (67% v 16%, P = .04). Though not significant, all valuable tumors with BRCA-1 mutations were HER-2/neu negative. In the entire cohort, there were no significant differences between BABC and non-BABC in 5-year relapse-free survival (60% v 78%, P = not significant [NS]), 5-year event-free survival (60% v 66%, P = NS), or 5-year overall survival. Conclusion: BABC seem to present with adverse molecular and histopathologic features when compared with cases not associated with BRCA-1 mutations. However, the prognosis of BABC appears to be similar to that of non associated cancer. Further studies of incident cases are necessary to define the independent prognostic significance of germline BRCA-1 mutations.